1. Field of the Invention
The present invention relates generally to the fields of medicine and biochemistry. More particularly, it concerns the use of oxytocin or oxytocin analogs either alone or in combination with other agents to treat bone disorders.
2. Description of Related Art
Bone mass increases rapidly during infancy, slowly throughout childhood, and substantially at puberty. At least half of adult bone mass is acquired during the teen years being influenced by genetics, nutrition, sex steroids, and exercise. By early adulthood, bone mass has peaked with loss occurring with aging. Continued bone mineral loss results in reduced bone mass, a condition known as osteopenia. Further decreases lead to osteoporosis, a disruption of normal bone architecture sufficient to produce atraumatic fractures. Osteoporosis generally presents in the elderly population, but also occurs in children and adolescents with chronic illness, malnutrition, or metabolic disorders. Hormone deficiencies, low body weight, anorexia nervosa, exercise associated amenorrhea, delayed puberty and cystic fibrosis are associated with osteopenia in young patients.
Osteoblast cells are responsible for bone mineralization and formation. Calcium, phosphate, magnesium, parathyroid hormone, calcitonin, estrogens, and 1,25 dihydroxyvitamin D.sub.3 are important positive regulators of osteoblast function. Bone demineralization and breakdown is carried out by osteoclasts cells, specialized acid secreting cells. The balance between these cells determines the amount of bone formation or breakdown at any given time of life. Osteopenia and osteoporosis are results of dominating osteoclast function causing bone resorption. Other indirect effects increasing bone resorption include inhibition of calcium intestinal absorption (excess glucocorticoids, cystic fibrosis, hyperthyroidism), inhibition of renal hydroxylation of 25-hydroxyvitamin D.sub.3 to the active 1,25-dihydroxyvitamin D.sub.3 (growth hormone deficiency, cystic fibrosis). Of particular note, no effective means of preventing glucocorticoid related bone loss has been established. Overproduction of glucocorticoids such as in Cushing's disease or prolonged treatment with glucocorticoids for diseases such as juvenile arthritis and childhood leukemias cause substantial bone loss in children.
Osteoporosis is characterized by low bone mass and a disruption of bone architecture that leads to an increased risk of fracture. It occurs in both men and women but most commonly among women following menopause, when the rate of bone resorption becomes greater than that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. It is estimated that 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip or wrist during their lifetime. Most major pharmaceutical companies, e.g. Glaxo Wellcome, Lily, Merck & Company, Wyeth-Aryst, Schering, etc., are developing compounds for the treatment of osteoporosis because these compounds are indicated for chronic daily use for the rest of an individual's life.
Known functions of oxytocin (OT) include smooth muscle contraction during birth (Soloff, 1989; Fuchs et al., 1982), milk letdown during lactation (Soloff et al., 1979), and prostaglandin release from endometrium/decidua and the amnion (Hinko and Soloff, 1993). These actions occur as very specifically timed events because of the upregulation of oxytocin receptors (OTRs). At term, myometrial OTRs rise just before birth and fall shortly after birth, whereas, OTRs in mammary myoepithelial cells which contract in response to OT release as a reflex to a baby's suckling, increase shortly after birth and remain elevated as long as suckling occurs. From these two examples, it is clear that the rise in OTR levels dictate tissue sensitivity to OT action, and the regulation of OTRs in tissues can be different. To date, known agents that cause an increase in OTR protein levels include estradiol in the uterus (Fuchs et al., 1983; Larcher et al., 1995) and glucocorticoids, and/or agents that elevate intracellular cyclic AMP levels in rabbit amnion (Hinko and Soloff, 1993).
A number of factors stimulate bone growth and differentiation through mechanisms that lead to increased prostaglandin (PG) synthesis. PGs are involved both in osteogenic and osteoclastic responses, and it is through that they are important for bone remodeling (Jee and Ma, 1997). Oxytocin is a potent activator of PG synthesis in the uterine endometrium and amnion (Fuchs et al., 1982; Flint et al., 1986; Moore et al., 1988; Hinko and Soloff, 1992). Although the actions of oxytocin have been regarded to be restricted to specific target cells in the female reproductive tract, mammary gland, and brain nuclei, there is emerging evidence for the presence of oxytocin receptors (OTRs) in other cell types, including thymocytes, fat cells, ovarian cells, and rat insulinomas (Zingg, 1996).
Current competing technologies for the treatment of osteoporosis include estradiol, calcitonin supplemented with dihydroxy Vitamin D.sub.3 and calcium, and bisphosphonates. Other therapies are also being developed, as discussed below. Yet, there is a clear need for alternative or synergistic therapeutic regimens for the improved treatment of bone loss associated with osteoporosis and osteopenias.